AMYOTROPHIC-LATERAL-SCLEROSIS ASSOCIATED WITH GENETIC ABNORMALITIES IN THE GENE ENCODING CU ZN SUPEROXIDE-DISMUTASE - MOLECULAR PATHOLOGY OF 5 NEW CASES, AND COMPARISON WITH PREVIOUS REPORTS AND 73 SPORADIC CASES OF ALS/

Molecular pathology has identified 2 distinct forms of neuronal inclus ion body in Amyotrophic Lateral Sclerosis (ALS). ALS-type inclusions a re skeins or small dense filamentous aggregates which can only be demo nstrated by ubiquitin immunocytochemistry (ICC). In contrast hyaline c onglomerates (HC) are large multifocal accumulations of neurofilaments . Previous reports have failed to clarify the distinction and relation ship between these inclusions. Correlation of molecular pathology with sporadic and familial cases of ALS will detect specific associations between molecular lesions and defined genetic abnormalities; and deter mine the relevance of molecular events in familial cases to the pathog enesis of sporadic disease. We describe the molecular pathology of 5 A LS cases linked to abnormalities of the SOD1 gene, in comparison with a series of 73 sporadic cases in which SOD1-gene abnormalities were ex cluded. Hyaline conglomerate inclusions were directed only in the 2 ca ses with the SOD1 I113T mutation and showed a widespread multisystem d istribution. In contrast ALS-type inclusions characterized sporadic ca ses (70/73) and were restricted to lower motor neurons. Hyaline conglo merates were not seen in sproadic cases. Confocal microscopic analysis and ICC shows that KC contain equally abundant phosphorylated and non phosphorylated neurofilament epitopes, indicating that phosphorylation is not essential for their formation. In contrast neurofilament immun oreactivity is virtually absent from typical ALS-type inclusions. The SOD1-related cases all had marked corticospinal tract and dorsal colum n myelin loss. In 4 cases the motor cortex was normal or only minimall y affected. This further illustrates the extent to which upper motor n euron damage in ALS is usually a distal axonopathy. Previously reporte d pathological accounts of SOD1-related familial ALS (FALS) are review ed. Hyaline conglomerates are so far described in cases with mutations A4V, I113T and H48Q. In only 1 of 12 cases (H48Q) reported were both HC and ALS-type inclusions present in the same case. These findings su ggest the possibility that the molecular pathology of neuronal inclusi ons in ALS indicates 2 distinct pathogenetic cascades.